In recent years, new .beta.-lactam antibiotic substances have been found in nature which have the same .beta.-lactam rings as penicillins and as cephalosporins, but which have different basic structures.
For example, naturally derived carbapenem compounds such as thienamycin isolated from the fermentation of Streptomyces cattleya (J. Am. Chem. Soc., vol. 100, p. 6491 (1978)), may be mentioned. Thienamycin has an excellent antibacterial spectrum and strong antibacterial activities over a wide range against Gram-positive bacteria and Gram-negative bacteria. Therefore, its development as a highly useful .beta.-lactam agent has been expected. However, thienamycin itself is chemically unstable, and it has been reported that it is likely to be decomposed by a certain enzyme in vivo such as renal dehydropeptidase I (hereinafter referred to simply as DHP-I), whereby the antibacterial activities tend to decrease, and the recovery rate in the urine is low (Antimicrob. Agents Chemother., vol. 22, p. 62 (1982); ibid., vol. 23, p. 300 (1983)).
Merck & Co., Inc. have synthesized many thienamycin analogs with an aim to maintain the excellent antibacterial activities of thienamycin and to secure chemical stability. As a result, imipenem: (5R,6S)-3-[[2-(formimidoylamino)ethyl]thio]-6-[(R)-1-hydroxyethyl]-7-oxo-1 -azabicyclo[3.2.0]hept-2-en-2-carboxylic acid monohydrate, obtained by formimidization of the amino group of thienamycin, has been practically developed as a pharmaceutical product (J. Med. Chem., vol. 22, p. 1435 (1979)).
Imipenem has antibacterial activities of an equal or higher level than thienamycin against various types of bacteria and has .beta.-lactamase resistance. Especially against Pseudomonas aeruginosa, its antibacterial activities are superior to thienamycin by from 2 to 4 times. Further, the stability of imipenem in the solid form or in an aqueous solution is remarkably improved over thienamycin.
However, like thienamycin, imipenem is decomposed by DHP-I in the human kidney, and therefore, it does not exhibit sufficient treatment effect on urinary-tract infections. Therefore, imipenem can not be administered alone and is required to be used in combination with a DHP-I inhibitor like cilastatin (J. Antimicrob. Chemother., vol. 12 (Suppl. D), p. 1 (1983)). In recent years, imipenem has been frequently used for the treatment and prophylaxis of infectious diseases. Consequently, highly methicillin-resistant Staphylococcus aureus which is resistant to imipenem and imipenem resistant Pseudomonas aeruginosa are increasing in the clinical field. Imipenem does not show adequate treating effects against these resistant bacteria.
The characteristic of the compounds of the invention is having the partial structure of S--C(.dbd.S)N in the substituent at the 2-position of the carbapenem skeleton, and carbapenem compounds having the partial structure are novel compounds not disclosed in literatures. Prior art disclosing or suggesting the invention has not been known at all.
.beta.-Lactam antibiotics exhibit selective toxicity against bacteria and show no substantial effects against animal cells. Therefore, they are widely used for treatment of infectious diseases caused by bacteria, as antibiotics having little side effects, and thus are highly useful drugs.
However, in recent years, highly methicillin-resistant Staphylococcus aureus (hereinafter, abbreviated as MRSA), methicillin-resistant coagulase negative Staphylococci (hereinafter, abbreviated as MRCNS) and resistant Pseudomonas aeruginosa have been isolated frequently from patients with the immunity decreased, as bacteria causing hardly curable infectious diseases. This has come into a large social problem. Further, recently, the strong toxicity of vancomycin, which is selectively used against MRSA, to the kidney, and the increasing resistance of pathogenic bacteria such as MRSA and MRCNS are becoming clinically serious problems. Accordingly, it is strongly desired to develop an antibacterial agent having improved antibacterial activities against such resistant bacteria, but .beta.-lactam antibacterial agents meeting such requirement have not yet been developed. With respect to carbapenem compounds, it is strongly desired to develop medicaments which have improved antibacterial activities against bacteria causing hardly curable infectious diseases, particularly against MRSA and MRCNS, improved stability against DHP-I, reduced toxicity against the kidney, and no side effect on the central nervous system.